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@ARTICLE{Reid:281531,
author = {Reid, Madigan M and Menon, Shreya and Liu, Hao and Zhou,
Haoyue and Hu, Zhirui and Frerich, Simon and Ding, Bella and
Oveisgharan, Shahram and Zhang, Zimo and Nelson, Sophia and
Apolonio, Amanda and Bennett, David A and Dichgans, Martin
and Pollard, Katherine S and Corces, M Ryan and Yang, Andrew
C},
title = {{H}uman brain vascular multi-omics elucidates disease-risk
associations.},
journal = {Neuron},
volume = {113},
number = {19},
issn = {0896-6273},
address = {[Cambridge, Mass.]},
publisher = {Cell Press},
reportid = {DZNE-2025-01149},
pages = {3143 - 3161.e5},
year = {2025},
abstract = {Cerebrovascular dysfunction underlies many neurological
disorders, yet how genetic variants in brain vascular cells
drive disease risk remains unknown. We developed
MultiVINE-seq to simultaneously profile RNA and chromatin
accessibility in vascular, perivascular, and immune cells
from 30 human brains. Mapping genome-wide association study
(GWAS) data to our multi-omic atlas linked thousands of GWAS
disease-risk variants to target cell types and genes,
including 2,605 previously unmapped. We found
cerebrovascular and neurodegenerative disease variants have
distinct mechanisms: cerebrovascular disease variants
disrupt extracellular matrix genes in endothelial, mural,
and fibroblast cells important for vessel structural
integrity, while Alzheimer's disease (AD) variants
dysregulate inflammatory adaptor proteins in endothelial and
immune cells. Notably, a lead AD variant enhances PTK2B
expression in brain CD8 T cells, providing genetic evidence
for adaptive immunity in AD pathogenesis. This work provides
a key resource for interpreting genetic risk and reveals how
variants in vascular cells drive divergent pathogenic
mechanisms across neurological diseases.},
keywords = {Humans / Genome-Wide Association Study / Brain: blood
supply / Brain: metabolism / Alzheimer Disease: genetics /
Genetic Predisposition to Disease: genetics /
Cerebrovascular Disorders: genetics / Female / Male / Focal
Adhesion Kinase 2: genetics / Focal Adhesion Kinase 2:
metabolism / Multiomics / Alzheimer's disease (Other) / T
cell (Other) / brain vasculature (Other) / cerebrovascular
disease (Other) / macrophage (Other) / microglia (Other) /
neurodegenerative disease (Other) / non-coding disease-risk
variants (Other) / single-cell multi-omics (Other) / stroke
(Other) / Focal Adhesion Kinase 2 (NLM Chemicals)},
cin = {AG Dichgans},
ddc = {610},
cid = {I:(DE-2719)5000022},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40730185},
pmc = {pmc:PMC12321221},
doi = {10.1016/j.neuron.2025.07.001},
url = {https://pub.dzne.de/record/281531},
}